tbuckley/cabot-search huggingface dataset:
Impact of subsequent therapies in patients (pts) with advanced renal cell carcinoma (aRCC) receiving lenvatinib plus pembrolizumab (LEN + PEMBRO) or sunitinib (SUN) in the CLEAR study.
Authors: Martin H Voss, Thomas Powles, Bradley Alexander McGregor, Camillo Porta, Viktor Grünwald, Jaime R. Merchan, Frederic Rolland, Pablo Maroto-Rey, Jeffrey C. Goh, Dongyuan Xing, Rodolfo F. Perini, Jodi McKenzie, Kalgi Mody, Robert J. Motzer
Journal: Journal of Clinical Oncology (2022)

4514 Background: In the open-label, randomized, phase 3 CLEAR study, LEN + PEMBRO had significant PFS (primary endpoint) and OS (key secondary endpoint) benefits over SUN among pts with aRCC in the 1L setting (Motzer 2021, NEJM). We evaluated PFS on next-line therapy (“PFS2”) and explored the effect of subsequent anticancer therapy on OS in the LEN + PEMBRO and SUN treatment arms of CLEAR. Methods: PFS2 was defined as time from randomization to disease progression (as assessed by investigator) on next-line treatment or death from any cause (whichever occurred first). PFS2 was evaluated in all pts randomly assigned to LEN 20 mg orally QD + PEMBRO 200 mg IV Q3W (n=355) or SUN 50 mg orally QD (4 wks on/2 wks off) (n=357) using Kaplan-Meier estimates, and compared between treatment arms via a log-rank test stratified by geographic region and MSKCC prognostic groups. The HR and corresponding CI were estimated using the Cox regression model with Efron’s method for ties, using the same stratification factors. A post hoc analysis accounting for the effect of subsequent anticancer therapy on OS (time from randomization to death from any cause) in the LEN + PEMBRO and SUN arms using 2-stage estimation was conducted. Results: Among pts who received subsequent anticancer therapy in the LEN + PEMBRO (n=117 pts) and SUN (n=206 pts) arms (Table), median time to next-line therapy was 12.2 mos (range 1.45–37.36) and 6.4 mos (range 0.39–28.52), respectively. Median duration of first subsequent anticancer therapy was 5.2 mos (range 0.10–30.23) in the LEN + PEMBRO arm and 6.8 mos (range 0.03–30.72) in the SUN arm. Among all pts, PFS2 was longer with LEN + PEMBRO than with SUN (median not reached vs 28.7 mos; HR, 0.50; 95% CI 0.39–0.65; nominal P&lt;0.0001); PFS2 rates at 24 and 36 mos are in the Table. The unadjusted OS HR for LEN + PEMBRO vs SUN (from the primary analysis [Motzer 2021, NEJM]) was 0.66 (95% CI 0.49–0.88); the HR for OS adjusted for subsequent therapy was 0.54 (bootstrap 95% CI 0.39–0.72). Conclusions: LEN + PEMBRO had a statistically significant and clinically meaningful benefit over SUN in the CLEAR study. These findings remained consistent after accounting for subsequent therapies, as evidenced by prolonged PFS2 and adjusted OS. Results further support LEN + PEMBRO as a standard of care in 1L aRCC. Clinical trial information: NCT02811861. [Table: see text]
Real-world analysis of the <i>EGFR</i> mutation detection in plasma ctDNA from patients with non-small cell lung cancer.
Authors: Chaolian Long, Kun Li, Zichen Liu, Nana Zhang, Xuya Xing, Liming Xu, Fei Gai, Nanying Che
Journal: Journal of Clinical Oncology (2022)

e21069 Background: Plasma sample has emerged as a promising surrogate sample for EGFR mutation detection in advanced non-small cell lung cancer (NSCLC). In clinical practice, whether EGFR variants in pretreatment plasma ctDNA of advanced lung cancer can predict prognosis in addition to guiding targeted therapy remains to be further explored. Methods: In this study, we retrospectively enrolled 315 NSCLC patients from Beijing Chest Hospital, 94.9% of whom were in stage IIIB-IV. EGFR gene mutation data from tissue detected by ARMS-PCR (Amoy Diagnostics, Xiamen, China) and paired plasma samples within one month of admission detected by SuperARMS-PCR (Amoy Diagnostics, Xiamen, China) were collected. The patients’ clinicopathological characteristics and treatment information were also collected for further analysis. Differences in PFS of targeted therapy between patients with positive and negative pretreatment plasma ctDNA EGFR mutation were compared. Results: EGFR-positive rate of tissue and plasma ctDNA was 65.1% (205/315) and 43.8% (138/315), respectively. L858R, 19-DEL, T790M, G719X, 20-INS, and L861Q mutations were detected in both samples. The sensitivity, specificity, PPV, NPV and concordance of ctDNA detection was 65.4%,96.4%, 97.1%, 59.9%, and 76.2%, respectively. In the study, patients’ pathological subtype was the factor affected plasma ctDNA EGFR alteration detection accuracy. The concordance in adenocarcinoma patients was obviously higher than that in non-adenocarcinoma (p = 0.02). 92 treatment naïve advanced patients with tissue EGFR mutation were received first and second-generation EGFR tyrosine kinase inhibitors (TKIs) therapies. 59.8% (55/92) patients also had EGFR mutation in plasma ctDNA, 40.2% (37/92) patients had no detectable EGFR mutations in plasma ctDNA. The median PFS in plasma ctDNA EGFR positive patients was 7.0 months versus 14.0 month in plasma ctDNA EGFR negative patients, with significantly difference (p = 0.004). Conclusions: Plasma sample could be a surrogate sample for molecular test when tissue sample was unavailable. The poor prognosis was observed in treatment naïve advanced NSCLC patients with baseline plasma EGFR mutation.
Feasibility of an explainable AI-based therapeutic recommendation-tool utilizing tumor gene expression profiles in advanced and refractory solid tumors.
Authors: Ouissam Al Jarroudi, Coralie Williams, Rita Santos, Armelle Dufresne, Valéry Attignon, Anthony Ferrari, Sandrine Boyault, Laurie Tonon, Séverine Tabone-Eglinger, Philippe Alexandre Cassier, Nadège Corradini, Armelle Vinceneux, Aurélie Swalduz, Alain Viari, Sylvie Chabaud, David Pérol, Mohammad Afshar, Jean-Yves Blay, Olivier Tredan, Pierre Saintigny
Journal: Journal of Clinical Oncology (2022)

1554 Background: Precision oncology aims to guide patient (pts) treatment decisions by matching biological features with available drugs. Extensive genomic analysis allows to identify an actionable alteration in 40-60% of patients. In a recent study of 50 pts with advanced refractory diseases included in PROFILER (NCT01774409), whole exome and fusion transcripts had a limited value over a 90-tumor gene panel (TGP) to increase molecular-based treatment recommendations (MBTR). Herein, we evaluated the feasibility, in the same cohort of pts, of the AI-transcriptional-based therapeutic recommendation-tool OncoKEM to guide treatment recommendations. Methods: 77 fresh frozen (FF) and/or FFPE samples including paired specimens for 53 pts with available RNA-Seq gene expression profiles were included. For each pts, a tumor transcriptional profile (TTP) was generated by identifying differentially expressed genes between the pts tumor and a cohort of matched healthy tissue. A large database of drug transcriptional signatures (DTS) was queried in order to identify a “reversal relationship” between the TTP and a DTS. A total of 205 drugs were ranked, including a subset of 61 FDA and/or EMA approved targeted therapies (aTT). Results: Most common diagnoses were breast cancers (21% of which 63% were TNBC), followed by ovarian cancers (OC, 18%) and soft-tissue sarcomas (STS, 13%). The median number of previous treatment lines was 4 (range: 1 - 10). Among the 77 tumor samples analyzed, 54 (70%) specimens led to the generation of an OncoKEM report, with no differences between FF and FFPE samples (p = 0.85). The overlap between the top 10 proposed drugs between paired FF and FFPE samples was 56% on average. All patients had at least 2 propositions (range: 2-9) of aTT among the top 10 ranked drugs in the Onco KEM reports. Most frequently proposed drugs among the top 10 were palbociclib, talazoparib, infigratinib in TNBC; bosutinib, sapanisertib, SAR125844 in OC; ipilimumab, cabozantinib, sapanisertib in STS. Among the 30 pts (79%) without any MBTR based on TGP/WES/fusion transcript analysis, all had at least 2 proposed aTT in the Onco KEM report (median: 4, range: 2-9). Top ranked drugs were MET (18%), VEGFR (12%), Abl (12%), FGFR (11%), PI3K/AKT/mTOR (11%), PARP (10%) and CDK4/6 inhibitors (7%). Conclusions: AI-transcriptional-based therapeutic recommendation-tool OncoKEM is feasible and has the potential to expand personalized cancer treatment in pts with advanced &amp; refractory diseases without tractable genomic alterations. The clinical relevance assessment is planned in an upcoming clinical trial.
Patient-derived xenografts of colorectal cancer for testing new pharmacological substances.
Authors: Georgiy Yu. Egorov, Anna S. Goncharova, D. V. Khodakova, L. Z. Kurbanova, Maria V. Mindar, Ekaterina V. Zaikina, Ekaterina Fedorovna Komarova, Evgeniy N. Kolesnikov, Aleksey Yu. Maksimov, Tanzila B. Katsieva, Roman E. Myagkov, Mikhail A. Averkin, Aleksandr V. Snezhko, Umar M. Gaziev, Nadezhda V. Nikolaeva
Journal: Journal of Clinical Oncology (2022)

e15612 Background: The purpose of this study was to create a patient-derived xenograft model of human colorectal cancer and to determine its histological and molecular characteristics, including the status of the KRAS, NRAS, BRAF genes and the presence of microsatellite instability factors. Methods: Biological materials obtained from tumors of 4 patients with colorectal cancer were used to create the first-generation in vivo model. The study was performed on immunodeficient Balb/c Nude mice (20 females aged 5-6 weeks). Subcutaneous xenografts were obtained by the implantation of a 3×3×3 mm donor tumor fragment to recipient animals under the skin of the right thigh, 5 samples from each patient. For the second, third and fourth PDX generations, mice of the same strain were used (n = 3 for each generation). All manipulations were performed in accordance with the rules for using laboratory animals. Genomic DNA was extracted from PDX samples, and mutations in exons 2, 3 and 4 of the KRAS and NRAS genes and BRAF V600 mutations were identified by direct sequencing. Microsatellite instability was determined by fragment analysis for five loci Bat-25, Bat-26, NR21, NR24, NR27. Results: Stable transplantable xenografts of colorectal cancer were obtained from two out of four patients. The average waiting time between implantation and growth of the first-generation xenograft was 28 days. The model was confirmed to reproduce the histotype, differentiation and mutational status of the KRAS, NRAS, BRAF genes and microsatellite instability similar to those of donor tumors. Conclusions: The results confirm the possibility of the model use for testing both new pharmacological substances with a cytotoxic effect and drugs based on monoclonal antibodies.
A retrospective cohort analysis of return-to-work outcomes for cancer survivors using a digital coaching intervention.
Authors: Yuri Yin-Moe Aung, Justin Smith, Kieran Ballurkar, Simonie Fox, Kate Tynan, Jonathon Lo, Raghav Murali-Ganesh, Michael J. Boyer
Journal: Journal of Clinical Oncology (2022)

1566 Background: Return-to-work (RTW) is a key unmet need for working age cancer survivors, with up to 40% failing to RTW 1 to 2 years post-diagnosis. This study sought to evaluate RTW outcomes of a multidisciplinary digital coaching intervention provided as routine employee support. Methods: A retrospective cohort analysis was conducted from October 2018 to February 2020 where cancer patients with more than 3 months absent from work were provided by their insurance carriers with a multidisciplinary intervention comprising digital resources and telephone calls with a health coach. A logit regression model was used to calculate a propensity score using covariates of age, gender, insurance benefit type, cancer diagnosis date and time from diagnosis. Participants were then matched on a 1:1 basis using the nearest-neighbour method without replacement to create a matched control group out of 1,856 participants who did not receive the intervention. Primary outcomes, derived from insurance-claims data as standard business practice, included rate and time to RTW, along with death and other reasons for claim closure. Results: 220 participants enrolled in the intervention, of which 125 met the criteria for analysis (median age 53, IQR 45-58, 91% female). These participants were matched with 125 controls (median age 53, IQR 47-59, 94% female). Median follow-up from cancer diagnosis was 79 weeks (IQR 60-106). Of the matched controls, 22 returned to work (17.6%) compared with 38 (30.4%) in the intervention group (P =.02). 19 matched controls died prior to claim closure (15.2%) compared with 13 in the intervention group (10.4%; P =.26). Finally, Kaplan-Meier method estimated median time for the first 15% of participants to RTW was 87.1 weeks for controls (CI 60.0-109.1 weeks) compared with 70.6 weeks for the intervention group (CI 52.6-79.6 weeks; P =.08). Conclusions: This study evaluated the impact of a digitally delivered coaching program in a real-world setting for cancer patients, demonstrating a 12.8% increase in RTW rate over 18 months compared to matched controls. These findings corroborate and add to the literature on cancer as a chronic and manageable disease in the workplace.
Comparison of survival outcomes between dostarlimab and comparator treatments (tx) in patients (pts) with advanced/recurrent (A/R) endometrial cancer (EC) in England: Matching-adjusted indirect comparisons (MAICs).
Authors: Scott Goulden, Kiera Heffernan, Fulya Sen Nikitas, Urmi Shukla, Craig Knott, Matthias Hunger, Ankit Pahwa, Rene Schade
Journal: Journal of Clinical Oncology (2022)

e17534 Background: Limited tx options exist for pts with A/R EC who progress on/after platinum-based chemotherapy (PBCT). This study compared survival outcomes of pts with A/R mismatch repair deficient (dMMR)/microsatellite instability-high (MSI-H) EC receiving dostarlimab in Cohort A1 of the single-arm, Phase I GARNET trial, with an equivalent real-world (RW) cohort receiving current tx in England. The primary objective compared second-line (2L) overall survival (OS) between cohorts; a secondary objective was time to tx discontinuation (TTD; proxy for progression-free survival). Methods: An overall-2L-tx RW cohort was established using National Cancer Registration and Analysis Service data. Five tx-specific RW cohorts were identified (tx received at 2L in &gt; 5% of pts) (Table). Clinical outcomes between GARNET and RW cohorts were compared using MAICs. Relevant prognostic variables were used to create 3 matching scenarios (SC): SC1: grade, histology, PBCT number; SC2: histology, PBCT number; SC3: race/ethnicity, stage at diagnosis, histology, prior surgery (MMR/MSI status not considered). OS was time from first dostarlimab dose (GARNET) or 2L RW tx (RW cohorts) to any-cause death; MAIC-adjusted hazard ratios (HR, 95% confidence interval [CI]) were estimated by weighted Cox proportional-hazards models. TTD after MAIC was summarized descriptively. Results: Effective sample size (ESS) assessed matching capacity; lower ESS in SC1 reduced its robustness (Table). Following matching, distributions of baseline characteristics were similar between cohorts. Across most matching scenarios, there was a lower risk of death in pts treated with dostarlimab compared to the overall RW cohort and for tx-specific RW cohorts (Table). Median TTD (months, 95% CI) was longer for pts treated with dostarlimab across all matching scenarios (SC1: 7.8 [4.1, not estimable (NE)]; SC2: 9.7 [5.5, NE]; SC3: 14.0 [6.4, 17.9]) than the overall RW cohort (3.4 [3.2, 3.4]). Conclusions: Results suggest that pts in GARNET with dMMR/MSI-H A/R EC receiving dostarlimab had better OS and longer TTD compared with pts receiving current 2L tx in England. Funding: GSK (217216; scott.r.goulden@gsk.com).[Table: see text]
First-in-human phase 1 trial of ELI-002 immunotherapy as treatment for subjects with Kirsten rat sarcoma (KRAS)-mutated pancreatic ductal adenocarcinoma and other solid tumors.
Authors: Shubham Pant, Muhammad Furqan, Raghad Muhsin Abdul-Karim, Vincent Chung, Craig E. Devoe, Melissa Lynne Johnson, Alexis Diane Leal, Haeseong Park, Zev A. Wainberg, Esther Welkowsky, Christopher M. Haqq, Eileen Mary O'Reilly, Colin D. Weekes
Journal: Journal of Clinical Oncology (2022)

TPS2701 Background: Mutations in KRAS and NRAS occur in one quarter of human solid tumors. The G12D allele is the most commonly occurring variant in pancreatic, colorectal, non-small cell lung, ovarian, biliary and gallbladder cancers. ELI-002 2P is an immunotherapeutic comprised of a lymph-node targeted amphiphile (AMP)-modified G12D and G12R mutant KRAS peptides together with an AMP-modified CpG oligonucleotide adjuvant. In preclinical models, ELI-002 demonstrated increased cytotoxic KRAS-specific T cells compared to non-lymph node targeted controls using the same peptide and adjuvant. Clinical evaluation of adoptively transferred KRAS-specific T cells demonstrated objective antitumor activity (Tran 2016). Circulating tumor (ctDNA) methodology permits identification of patients with minimal residual disease (MRD) following locoregional treatment. In MRD setting, immunotherapy is anticipated to succeed as the ratio of effector T cells to target tumor cells is maximized prior to bulk visible disease. The AMPLIFY-201 study (NCT04853017) is evaluating ELI-002 in patients with KRAS mutated solid tumors with MRD. Methods: AMPLIFY-201 is an open-label, dose-escalation and expansion phase I, first in human, trial evaluating ELI-002 2P in patients with KRAS mutated tumors with MRD following standard of care therapy. The initial phase I cohort enrolls patients with colorectal and pancreatic cancer to receive multiple doses of AMP-peptides 70mcg each (1.4 mg total) admixed with AMP-CpG 0.1 mg, administered once every two weeks. Subsequent phase I cohorts will enroll patients with RAS-mutated pancreatic, colorectal, non-small cell lung, ovarian, bile duct or gallbladder cancer, who will receive a fixed dose of AMP-peptides 70 mcg each, together with escalating doses of AMP-CpG. Safety and efficacy will be summarized with descriptive statistics. The maximum tolerated dose (if any) and the recommended phase II dose (RP2D) will be determined with the dose-response activity of ELI-002 2P in eliciting functional KRAS-specific T cells. Preliminary antitumor activity will be characterized using changes from baseline in ctDNA, serum biomarkers appropriate for tumor type, and progression free survival time. Eligibility includes patients who have received standard of care locoregional treatment according to NCCN guidelines and whom have MRD persistence or relapse (ctDNA positive). Patients with colon and pancreas cancer with Stage IV oligometastatic disease (&lt; 3 lesions in one organ) rendered surgically free of disease and with MRD, are also eligible. The dose escalation portion of the study is currently enrolling. Clinical trial information: NCT04853017.
Safety and efficacy of monoclonal antibodies and tyrosine kinase inhibitors in advanced breast carcinoma.
Authors: Usman Ali Akbar, Mounica Vorla, Aqsa Ashraf, Keerthi Poladi, Shaheryar Qazi, Ammar Yaser Dab, Hafsah Ijaz, Ali Sibtain Azhar, Syeda Manahil Haider Jeoffrey, Muhammad Ali Ali Akhtar, Ali Momin
Journal: Journal of Clinical Oncology (2022)

e13017 Background: Novel drugs that target HER2 receptors have shown promise in the treatment of Advanced breast carcinoma (BC). We study here the safety and efficacy of select monoclonal drugs (Mab) and tyrosine kinase inhibitors (TKIs) in the treatment of advanced BC. Methods: Following the PRISMA guidelines, we searched the literature on PubMed, Cochrane, Embase &amp; clinicaltrials.gov. A total of 1054 articles were screened, and 6 studies were included. Results: In a phase III trial comparing Margetuximab (MAR) vs Trastuzumab (TRA), the overall survival (OS) and Progression free survival (PFS) was superior for MAR (21.6m Vs 19.8m &amp; 5.7m Vs 4.4m respectively). However, the side effect profile is comparable for both drugs.Neutropenia (50 %) was a key problem in an ongoing trial including Zenocutuzumab (ZENO), resulting in dosage reduction. Similarly, phase III trials incorporating TKIs such as Neratinib (NER) and Tucatinib (TUC), there was improved OS (21m Vs 18.7, 24.7m Vs 19.2m respectively) as compared to Standard of care and chemotherapy. Regarding safety profile, these therapies are generally well tolerated with manageable side effects as listed in the table. Conclusions: Both monoclonal antibodies and tyrosine kinase inhibitors show clinically significant benefits in advanced HER2 positive breast carcinoma. However, more evidence and randomized clinical trials are needed to further establish their role in this rapidly evolving field.[Table: see text]
Change in breast cancer risk perception related to perceived COVID-19 risk: A WISDOM sub-population analysis.
Authors: Tina Qing Huang, Ryan Baxter-King, Arash Naeim, Aaron Rudkin, Lynn Vavreck, Karen Sepucha, Leah P. Sabacan, Laura Esserman, Neil Wenger
Journal: Journal of Clinical Oncology (2022)

e24135 Background: Obstacles to access to care due to the perceptions of the risk posed by COVID-19 have led to unprecedented disruptions in cancer care. Yet, little is understood about whether perceived COVID-19 risk influences perceptions of cancer risk. We examined how COVID-19 risk perception was associated with perceptions of breast cancer risk over one year of the pandemic among women enrolled in the WISDOM study, a PCORI-funded pragmatic trial testing risk-based cancer screening that began before the pandemic. Methods: We conducted four longitudinal surveys among the 13,002 women enrolled in the WISDOM study from May - December 2020. Responses from 8,285 women are eligible for inclusion in this analysis leading to a total sample size of 16,859 survey responses. Surveys were conducted online and asked women’s perceived lifetime chance of developing breast cancer (0-100%). COVID-19 risk perception was reported on a 5-point scale from Very Low to Very High. We computed the difference between breast cancer risk perception at each COVID-19 survey to pre-COVID breast cancer risk perception, measured as a secondary aim of the WISDOM study, and compared that to COVID-19 risk perception at each time point. Results: Across the four survey waves, most women perceived low COVID risk: 29% very low, 42% moderately low, 23% neither high nor low and 6% high or very high. Overall, breast cancer risk perception declined for those with very low COVID-19 risk perception and rose for women in the highest levels of COVID-19 risk perception. However, changes in breast cancer risk perception associated with COVID risk perception were small. For example, in survey wave 4, breast cancer risk change was -2.4% very low, -1.4% low, 2.5% not high or low and 3.1% high or very high. (Table). Conclusions: Among women participating in a pragmatic trial testing risk-based cancer screening, COVID risk perception had a small relationship with change in breast cancer risk perception. Change in breast cancer risk perception paralleled COVID-19 risk perception. This calls for exploration of the underpinnings of these risk changes and may have implications for changes in cancer screening behavior related to COVID-19.[Table: see text]